Ulnohumeral debridement arthroplasty: a retrospective study and midterm outcome results.

INTRODUCTION: Osteoarthritis of the elbow (OA) is an uncommon entity. In most cases, it can be attributed to long-standing occupational stress, previous injury, loose bodies in the joint. Patients complain of pain and stiffness at the extremes of movements. This can be caused by degenerative changes at the radio-capitellar, ulnohumeral joint or due to ulnar nerve symptoms. We perform the Outerbridge-Kashiwagi (OK) procedure at our institution for the management of problematic primary elbow osteoarthritis. OBJECTIVES: The purpose of this retrospective study was to evaluate the outcome of ulnohumeral arthroplasty in 13 elbows which was done over a period of 6 years in our institution. Range of movement (ROM) and pain were measured, and X-rays were assessed. METHODS: Thirteen patients who underwent ulnohumeral arthroplasty between 2006 and 2012 were included in the study. There were 11 males and 2 females with an average age of 54 years (35-78), with a mean follow-up of 4 years. RESULTS: The pain score improved from 8 (6-10) to 2 (0-2) using the visual analogue scale. Eleven patients were completely pain-free. There was an improvement of 27° in the flexion extension arc. There were no complications. CONCLUSIONS: Ulnohumeral arthroplasty can yield good pain relief and moderate improvement in the range of movement. It is a relatively easy and safe procedure to perform in patients with primary degenerative osteoarthritis of the elbow.

Divergent kinetics differentiate the mechanism of action of two HDAC inhibitors.

Histone deacetylases (HDACs) play diverse roles in many diseases including cancer, sarcopenia, and Alzheimer's. Different isoforms of HDACs appear to play disparate roles in the cell and are associated with specific diseases; as such, a substantial effort has been made to develop isoform-selective HDAC inhibitors. Our group focused on developing HDAC1/HDAC2-specific inhibitors as a cancer therapeutic. In the course of characterizing the mechanism of inhibition of a novel HDAC1/2-selective inhibitor, it was determined that it did not exhibit classical Michaelis-Menten kinetic behavior; this result is in contrast to the seminal HDAC inhibitor SAHA. Enzymatic assays, along with a newly developed binding assay, were used to determine the rates of binding and the affinities of both the HDAC1/2-selective inhibitor and SAHA. The mechanism of action studies identified a potential conformational change required for optimal binding by the selective inhibitor. A model of this putative conformational change is proposed.

The optimization of aminooxadiazoles as orally active inhibitors of Cdc7.

A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 µM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.

Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism.

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.

Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups.

Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.

Quinolinone-based agonists of S1P1: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 µM, 120% efficacy; 5: EC(50)=0.070 µM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 µM; 5: EC(50)=1.5 µM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

Body composition changes during the first two years of university.

OBJECTIVE: Changes in body weight, composition, and shape were investigated in male and female college students between the freshman and sophomore years. METHODS: Changes in weight, body mass index (BMI), percent and absolute body fat and fat-free mass (via bioelectrical impedance), and waist circumference (via body scans) were assessed over the freshman and sophomore years (2007-2009) among 120 students attending a Southern public university. RESULTS: Weight (2.5 and 1.7 lbs) and BMI gains (0.3 and 0.3 kg/m(2)) did not significantly differ between the freshman and sophomore years, respectively. Significantly more percent body fat and fat mass were gained during the freshman (1.9% and 3.3 lbs, respectively) than the sophomore year (0.0% and 0.6 lbs, respectively). Females lost significantly more fat-free mass during the freshman (-0.8 lb) than during the sophomore year (1.0 lb). Changes in waist circumference and weight were significantly correlated. Increases in the percentages of females classified as overweight and with unhealthy body fat amounts and waist circumferences were observed. CONCLUSION: While the sophomore year was characterized by slightly healthier body composition changes than the freshman year, the gains in weight, fat mass, and waist circumference measurements suggest increased health risks for many college females.

Evidence-based practice implementation strategy: the central role of the clinical nurse specialist.

The Hospital of the University of Pennsylvania Model of Excellence in Nursing Professional Practice serves to fully integrate the role of the clinical nurse specialist (CNS) in the implementation of evidence-based care and the role of organizational change agent. In this role, the CNS is responsible for the identification and remedy of system-wide challenges to optimal quality care, mentorship of clinical nurses both as clinicians and as leaders, and enhancement of interdisciplinary partnerships. Integrating the CNS role as the nursing department knowledge keepers, knowledge seekers and knowledge disseminators able to proactively develop and enhance interdisciplinary partnerships required systematic educational sessions and use of outcome measurement tools. Resources have included role development seminars, individual mentoring and standardization of role expression, across service lines. Development and implementation of an outcome measurement tool has served to further quantify the contribution of the CNS and standardized role implementation across service divisions. This dedication of resources has resulted in a significant number of unit-based and system-wide CNSs, serving as a significant support to the clinical nurse's practice and leadership development. This article will describe some of the processes used to enhance the role of the CNS implementing change and practice improvement at the Hospital of the University of Pennsylvania.

The discovery of an orally efficacious positive allosteric modulator of the calcium sensing receptor containing a dibenzylamine core.

The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.

An organized, comprehensive, and security-enabled strategic response to the Haiti earthquake: a description of pre-deployment readiness preparation and preliminary experience from an academic anesthesiology department with no preexisting international disaster response program.

BACKGROUND: On Tuesday, January 12, 2010 at 16:53 local time, a magnitude 7.0 M(w) earthquake struck Haiti. The global humanitarian attempt to respond was swift, but poor infrastructure and emergency preparedness limited many efforts. Rapid, successful deployment of emergency medical care teams was accomplished by organizations with experience in mass disaster casualty response. Well-intentioned, but unprepared, medical teams also responded. In this report, we describe the preparation and planning process used at an academic university department of anesthesiology with no preexisting international disaster response program, after a call from an American-based nongovernmental organization operating in Haiti requested medical support. The focus of this article is the pre-deployment readiness process, and is not a post-deployment report describing the medical care provided in Haiti. METHODS: A real-time qualitative assessment and systematic review of the Hospital of the University of Pennsylvania's communications and actions relevant to the Haiti earthquake were performed. Team meetings, conference calls, and electronic mail communication pertaining to planning, decision support, equipment procurement, and actions and steps up to the day of deployment were reviewed and abstracted. Timing of key events was compiled and a response timeline for this process was developed. Interviews with returning anesthesiology members were conducted. RESULTS: Four days after the Haiti earthquake, Partners in Health, a nonprofit, nongovernmental organization based in Boston, Massachusetts, with >20 years of experience providing medical care in Haiti contacted the University of Pennsylvania Health System to request medical team support. The departments of anesthesiology, surgery, orthopedics, and nursing responded to this request with a volunteer selection process, vaccination program, and systematic development of equipment lists. World Health Organization and Centers for Disease Control guidelines, the American Society of Anesthesiology Committee on Trauma and Emergency Preparedness, published articles, and in-country contacts were used to guide the preparatory process. CONCLUSION: An organized strategic response to medical needs after an international natural disaster emergency can be accomplished safely and effectively within 6 to 12 days by an academic anesthesiology department, with medical system support, in a center with no previously established response system. The value and timeliness of this response will be determined with further study. Institutions with limited experience in putting an emergency medical team into the field may be able to quickly do so when such efforts are executed in a systematic manner in coordination with a health care organization that already has support infrastructure at the site of the disaster.

Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2).

A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.

Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.

Calcium sensing receptor activators: calcimimetics.

The calcium sensing receptor (CaR) is a G protein-coupled receptor (GPCR) that plays a fundamental role in serum calcium homeostasis. The CaR is expressed on the chief cells of the parathyroid gland and is responsible for controlling the secretion of parathyroid hormone (PTH). PTH acts on several organs including the bone, kidney, and intestine to tightly regulate the concentration of serum calcium. Substances other than calcium that activate the CaR are referred to as calcimimetics. Calcimimetics that bind to the CaR as agonists are referred to as type I. Type II calcimimetics bind to a site that is distinct from the physiological ligand and function as positive allosteric modulators of the CaR. Type II calcimimetics amplify the sensitivity of the CaR to serum calcium and are thus able to lower the concentration of serum PTH. Calcimimetics are being pursued as therapeutics for the treatment of disorders that are characterized by elevated levels of PTH such as primary and secondary hyperparathyroidism (primary HPT and secondary HPT). In this review, we provide an overview of key results in the discovery of cinacalcet HCl (Sensipar in the US, Mimpara in Europe). In addition, other recently disclosed type II calcimimetics are discussed.

Evaluating the effects of herbicide drift on nontarget terrestrial plants: A case study with mesotrione.

Nature of exposure is a fundamental driver in nontarget terrestrial plant risk assessment for pesticides; consequently a novel study was designed to generate field-based drift exposure and evaluate corresponding biological effects of the herbicide mesotrione. The approach used a combination of US guideline drift reduction technology and vegetative vigor approaches. In each of 3 independent replicate spray application trials, 10 pots each of lettuce and tomato were placed at distances of 10, 20, 30, 40, and 50 ft (∼3, 6, 9, 12, and 15 m) from the downwind edge of the spray boom. Each application was conducted using a commercial 60-ft (18-m) boom sprayer fitted with TeeJet® Technologies TTI110025 nozzles, with a nominal application rate of 0.2 lb a.i./A (224 g a.i./ha). The environmental conditions required by the protocol (air temperature 10-30 °C and wind perpendicular to the swath (±30°) blowing toward the plants at a mean wind speed of ≥10 mph [≥4.5 m/s] measured at 2.0 m above the ground) were met for each application. Following exposure, plants were transferred to a greenhouse for the 21-d vegetative vigor phase of the study. Symptoms of phytotoxicity and plant height were assessed at 7, 14, and 21 d after treatment. On completion of the 21-d after treatment assessment, all plants were harvested and dried in an oven to determine shoot dry weight. The biological data indicated that no statistically significant effects were observed at a distance of 30 ft (∼9 m) from mesotrione drift at wind speeds of ≥10 mph (10.9-12.4 mph); this endpoint (30 ft) is defined as the no observed effects distance (NOED). Environ Toxicol Chem 2017;36:2465-2475. © 2017 SETAC.

Monitoring the effects of thiamethoxam applied as a seed treatment to winter oilseed rape on the development of bumblebee (Bombus terrestris) colonies.

BACKGROUND: The development of bumblebee (Bombus terrestris audax) colonies that had foraged for 5 weeks on flowering winter oilseed rape grown from seed treated with thiamethoxam (as Cruiser OSR) was assessed (two control, one treated field). Colony development was evaluated by monitoring the colony mass, forager activity was assessed, both at the hive and within the crop, and the contribution of oilseed rape to the pollen stored within the colony was analysed. RESULTS: Pollen collected from the treated crop contained residues of 1.0 µg thiamethoxam kg(-1) and 3.0 µg CGA322704 (metabolite likely equivalent to clothiandin) kg(-1) , and nectar contained residues of 1.8 µg thiamethoxam kg(-1) and no metabolite. No residues of thiamethoxam or CGA322704 were detected in samples from the control fields. Up to 93% of bumblebee collected pollen sampled from within the colonies originated from oilseed rape, and B. terrestris were observed actively foraging on all the fields. Colonies on all three fields showed similar rates of mass gain during the exposure phase and comparable production of gynes and drones. CONCLUSIONS: B. terrestris colonies placed adjacent to a field of flowering oilseed rape grown from thiamethoxam-treated seed developed at a comparable rate with colonies placed adjacent to oilseed rape grown from untreated seed. © 2015 Society of Chemical Industry.

Return to driving after total knee arthroplasty.

OBJECTIVE: The aim of this study was to ascertain the duration from time of surgery to resumption of driving after total knee arthroplasty (TKA) and to examine recommendations in the literature. METHODS: All patients who underwent primary unilateral TKA and were driving within 6 months preceding the arthroplasty were included. The patients' age, gender and side of the TKA were noted. The time taken to resume driving by each patient as well as the type of vehicle were noted. RESULTS: Ninety-eight patients were included in our survey. Fifty-five patients (56%) underwent TKA on their left knee and 94 (96%) were manual car drivers. Seventy-seven patients (79%) were able to resume driving within 6 weeks of TKA; 18 patients (18%) were able to do so at Week 12 postoperatively. The remaining 3 patients (3%) did not feel confident enough to drive at Week 12 postoperatively. No patient reported deterioration in driving ability, whereas 27 patients (27%) felt a subjective improvement in their driving ability. CONCLUSION: The vast majority of patient resumed driving by 6 weeks postoperatively. Only a small number did not return to regular driving. Patients are advised to resume driving after 6 weeks but should wait until they feel comfortable and confident enough to do so.

Obliteration of the medullary canal in an atypical bisphosphonate-related femoral fracture.

We present a case of a patient with a bisphosphonate-related atypical femoral fracture. Her surgical management was complicated by obliteration of the medullary canal, which prohibited the passage of an intramedullary nail. The relevant literature is discussed.

Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability.

The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1α endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1α endonuclease as well as cellular IRE1α. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1α was obtained. Screening of native tumor cell lines (>300) against selective IRE1α inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1α activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.

Quality as a system property: section 646 of the Medicare Modernization Act.

The Medicare Trustees' 2004 report indicates that the Part A Hospital Insurance trust fund will be exhausted by 2019. Medicare's sustainable growth rate (SGR) formula for physician reimbursement is widely recognized as being flawed; if it is not reformed, it may result in reduced access to physician services for beneficiaries. MedPAC proposes an alternative to the SGR formula that involves explicit consideration of Medicare program objectives and ensures that payments for physician services be adequate to maintain access. Section 646 of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) of 2003 may provide answers regarding providing high-quality care in fee-for-service Medicare.

Enantiomeric resolution of a novel chiral cannabinoid receptor ligand.

The enantiomeric resolution of a racemic novel cannabinoid receptor ligand conformationally restricted at the southern aliphatic chain was accomplished using a ChiralPak AD column. Both enantiomers were tested for their competitive binding to the rat brain CB1, mouse spleen CB2 and human CB2 receptors. The levorotatory isomer showed exceptionally high affinity for the CB1 receptor with a seven-fold selectivity over CB2.